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*
Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Ghent, Ghent, Belgium; and
Laboratory of Vertebrate Neurobiology, The Rockefeller University, New York, NY 10021
Lethal hepatitis can be induced by an agonistic anti-Fas Ab in
normal mice or by TNF in mice sensitized to
D-(+)-galactosamine or actinomycin D. In all three models,
we found that apoptosis of hepatocytes is an early and necessary step
to cause lethality. In the three models, we observed activation of the
major executioner caspases-3 and -7. Two acute-phase proteins,
1-acid glycoprotein and
1-antitrypsin, differentially prevent lethality:
1-acid glycoprotein protects in both TNF models and not
in the anti-Fas model, while 1-antitrypsin confers
protection in the TNF/D-(+)-galactosamine model only. The
protection is inversely correlated with activation of caspase-3 and
caspase-7. The data suggest that activation of caspase-3 and -7 is
essential in the in vivo induction of apoptosis leading to lethal
hepatitis and that acute phase proteins are powerful inhibitors of
apoptosis and caspase activation. Furthermore, Bcl-2 transgenic mice,
expressing Bcl-2 specifically in hepatocytes, are protected against a
lethal challenge with anti-Fas or with
TNF/D-(+)-galactosamine, but not against TNF/actinomycin D.
The acute-phase proteins might constitute an inducible
anti-apoptotic protective system, which in pathology or disturbed
homeostasis prevents excessive apoptosis.
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